When animals are exposed to different trace metals for prolonged periods of time, each metal produces a biological response profile which specifically characterizes exposure to that metal. The objective of these studies is to assess and characterize response profiles based on a thorough understanding of subcellular mechanisms of metal toxicity and specifically to (1) define and correlate ultrastructural and biochemical responses in vivo which characterize exposure to toxic trace elements and (2) develop early, specific, and sensitive biochemical testing procedures that may be used to evaluate human populations exposed to environmentally important trace elements. Specific metals and areas of interest include the biochemical effects of cadmium and lead on mitochondrial and lysosomal structure and function. Studies have shown that renal lysosomes play a central role in mediating the uptake and toxicity of circulation cadmium-thionein to renal proximal tubule cells and in the development of the attendant low molecular weight proteinuria. Cytosolic lead-binding components were found in target tissues for this element and were partially characterized by gel chromatography and electrophoresis. The binding components appear to be a major initial intracellular compartment for lead entering the cells of target organs.